Aqueous deficiency dry eye (ADDE) is characterized by a lack of tear secretion from the lacrimal glands (LG). Currently there is no cure and no satisfactory treatment for ADDE. One of the challenges of understanding the mechanism of human ADDE pathogenesis is the inability to perform the biological and molecular studies prior to obvious clinical signs. As a result, it remains difficult to understand the precise steps of disease development. The goal of this proposal is to track stem and progenitor cell fate during tissue maintenance and disease and to identify the optimum progenitor cells to repair the diseased LG. We propose to use the recently developed TSP-1-/- mice that fully mimic the chronic development of autoimmune dry eye disease with loss of function preceding cellular inflammatory cell infiltration. We propose the novel idea that the LG has two functionally distinct progenitor cell populations: EPCP and MECP of the adult LG contains common (or bipotent) stem/progenitor cells able to give rise to both EPC and MEC cell lineages. We will follow each cell lineage in vivo and determine whether the MECP's or EPCP's have a common stem/progenitor cell producing acinar, ductal, and MEC's or a lineage specific progenitor. We will also investigate the fate of MECP's and EPCP's cells in `diseased' LG's and test the ability of normal MECP's and EPCPs to restore the function of `diseased' LG's. Our recent data shows that among c-kit-positive epithelial cell (EPC) populations sorted from mouse LG the c-kit+dim/EpCAM+/Sca1-/CD34-/CD45- cells are a putative epithelial (acinar and ductal) cell progenitor (EPCP) population. Isolated EPCP's express pluripotency factors and markers of the epithelial cell lineage Runx1 and EpCAM and form branches when grown in reaggregated 3D cultures. When transplanted into injured or diseased LG's, they restore the functional acinar and ductal epithelial component of the LG. We also found that myoepithelial cells (MEC's) have a high level of plasticity and are able to differentiate into neuronal, endothelial, and MEC lineages Availability of new tamoxifen- inducible epithelial and myoepithelial lineage specific-reporter mice allows us to directly isolate MEC's/MECP's and EPC's/EPCP's from the healthy and diseased LG's for morphological, functional and gene expression analyses, and also for progenitor cell purification, and transplantation. Our study will provide proof of concept for use f LG progenitor cells in cell replacement therapy for dry eye diseases that have no effective treatment or cure. Our work would also open up new therapeutic possibilities to treat ADDE.